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93
Chapter 3
Partial, Selective and Tandem Reductions of Esters of Garcinia and Hibiscus Acids Using Boranes and
Borohydrides. The 11B NMR Spectroscopy based Mechanistic Insight into Reduction Reactions of Hydroxy Esters
3.1 Introduction
3.1.1 Boron and Borohydrides
Neutral boron-containing compounds are widely used in organic and
inorganic molecular chemistry. Most of these species have Lewis acidity because
of a vacant p-orbital that accepts a lone pair from a Lewis base (Figure 3.1)202
BRR R
LBB
RR R
LB
LB=Lewis base
Figure 3.1
The uniqueness of boron is its existence as complex clusters in elemental
form, which is reflected in its high physical constants (mp 2079 °C, bp 4000 °C).
This is due to the formation of stable covalently bonded molecular networks.
Electron deficiency in BX3, BH3, and higher boron compounds such as B10H14 has
enormous chemical implications, including the existence of large numbers of
cluster compounds. For instance, polyhedral boranes, carboranes, metalloboranes,
boron nitrides, and heteroboranes. Another important aspect of boron is that it
forms a very complex series of hydrides. Carbon is the only other element which
forms similar hydrides. However, the structures of the boron hydrides (boranes)
are quite different from those of carbon hydrides (hydrocarbons). Instead of rings
and chains, they form cages and clusters.
Boranes and borohydride reagents have found utility in the synthesis of a
number of pharmaceuticals and other compounds. These reagents are mainly
classified as borane complexes, organoboranes and borohydrides. Due to the
electrophilic nature of borane and the ease of formation of complex with the
electron-rich center of the functional group, reductions with borane are very
94
selective and specific and exhibit a number of synthetic applications.203 The
Chloroborane–Methyl Sulphide204 (BCl3.SMe2) permitted the one-pot synthesis of
diboraadamentane via hydroboration of cyclooctatetraene followed by
depolymerisation. Development of 9-BBN-Pyridine complex (a boron reagent
stable in air) resulted from a quest for more selective reducing agent that could
distinguish between aldehydes and ketones.205a Direct oxidation of
organoboranes by Pyridinium Chlochromate (PCC) to aldeydes gave an
additional route to convert organoboranes to synthetically useful molecules.
Thexylborane opened a new path for the synthesis of unsymmetrical ketones
from olefins. Stepwise reduction/ hydroboration of haloboranes enabled the first
convenient synthesis of unsymmetrical organoboranes.205 Stereo specific
synthesis of cis- and trans- olefins via organoboranes opened options for
pheromone synthesis. The asymmetric hydroboration reactions employing
diisopinocamphenyl borane, (IPc2BH) pave way towards the development of
several chiral boron reagents for the preparation of enantiomerically enriched
compounds.205 Some other highlights include asymmetric reductions, Suzuki-
Miyaura cross-coupling,206 Matteson’s boronic ester homologation207 and Brown’s
asymmetric crotylboration.208 In the last 25 years, the development of new
synthetic methodologies using boranes has allowed the synthesis of very
complex molecular structures in high selectivity and excellent overall yields.
An account of the versatility of boron reagents towards organic functional
groups are available.209 Methods for the reduction of select class of functional
groups namely, carboxylic acids, esters and anhydrides have been summarized
by Larock.210 A review covering the diversity of boron in synthetic applications at
the pharmaceutical and industrial scales203 as well as a general review covering
large scale processes for carbonyl reduction has appeared recently.211
3.2 Tuning of Boron Reagents
The catalytic effect of ethers in the hydroboration reaction led to the
development of more stable borane ligand complexes (BH3-L) as the preferred
borane sources at commercial scale. Borane adducts of Lewis bases such as
tetrahydrofuran (THF), Borane Dimethyl Sulfide (BMS) and some aromatic and
hindered amines have been used very effectively for hydroboration of double and
triple bonds as well as in reductions of other functional groups.203
95
The strength of the Lewis base determines the reactivity of the borane
complex. Borane tetrahydrofuran complex (BTHF) is the most reactive. At the
other extreme, numerous amine boranes possess low reactivity even toward
proton sources such as water, alcohols and carboxylic acids. Sulfide boranes,
dialkylaniline boranes and bulky amine boranes are intermediate in reactivity. The
amine and sulfide borane complexes offer concentration advantages over BTHF.
For example, BMS is 10 times more concentrated than BTHF. Both amine and
sulfide borane complexes are more stable than BTHF at ambient or higher
temperatures. BH3·SMe2 (BMS) is the most commonly used stoichiometric
reducing agent despite the stench problems associated with its large-scale use,
such as the need for efficient scrubbing and disposal of large volumes of waste
contaminated with dimethyl sulfide (SMe2). Other borane sources include
BH3·Et2NH, catecholborane, and BH3· Et2NPh. BH3·Amine complexes offer several
advantages such as (a) storage at ambient temperature (unlike BTHF which
requires refrigeration) (b) lack of stench (unlike BMS) (c) lack of pyrophoricity.203
One of the most desirable characteristics of boranes is the mildness of the
reaction conditions required for reductions. The chemoselectivity of borane
reduction is highly valued. Aldehyde, ketone, amide and carboxylic acid
functional groups are effectively reduced by borane complexes in the presence of
other functional groups. Strictly anhydrous conditions are required to obtain high
enantioselectivities since even very slight amount of water can have a huge
impact on the selectivity of asymmetric reduction using borane reagents.203
3.2.1 Reduction of carboxylic acids to alcohols
Several methods have been reported for the reduction of carboxylic acids
to alcohols. The carboxylic acid functional group is reduced at a faster rate by
borane complexes212 than most other groups, including non conjugated alkene,
and is therefore the reagent of choice for the reduction of carboxylic acids.
Commonly, halogen, nitro, carbamate and ester groups remain intact under the
reduction of a carboxylic acid using borane reagents. The common reagents for
this purpose are either as BTHF213 (1 M in THF) or BMS.214 An aqueous, acidic
workup (e.g., HCl, citric acid) usually follows reduction with BTHF. For reductions
with BMS, THF and CH2Cl2 are the solvents of choice, and either aqueous,
96
methanolic KF214a or aqueous NaOH quenches have been employed after
reaction completion.
The mechanism of the reduction of carboxylic acid to alcohol is known to
occur stepwise. Initially, the acidic proton reacts giving diacyloxyborane
intermediate 253 and hydrogen is evolved (Scheme 3.1).203 The carbonyl group
in 253 is then reduced with two hydrides from free borane in the solution.
Redistribution occurs such that the intermediate before protic quenching is a
trialkoxyboroxin 255. Three hydride equivalents are required for the carboxylic
acid reduction since, in the redistribution process, borane is released from the
intermediates. The amount of borane required for the process could be minimized
by the addition of BF3 to the reaction mixture. Table 3.1 shows the examples of
reduction of carboxylic acids using borane reagents in the presence of other
groups such as ester and lactone carbonyls.203
R OH
O "BH 3"R O
O
BH
2
"BH 3"R O
OBH2
BH
2
"BH 3" OB
OBO
BOCH2R
RH2CO OCH2R
252 253 254 255
Scheme 3.1 Mechanism of carboxylic acid reduction i nvolving borane reagents
97
Table 3.1 Reduction of carboxylic acids using boran e reagents
Starting material Reagents and conditions
Product Yield (%)
References
Br
SHO
EtO
O
O
OO
256
BTHF,0-10 °C, THF
Br
SHO
EtO
O
OO
257
98 215
OHO2N
O
OH
258
2 equiv.BTHF,1 equiv.BF3-
etherate, RT OHO2N
OH
259
96 216
N
OOH
OO-t-Bu
260
BTHF, 0 °C to RT, THF
N
OH
OO-t-Bu
261
96 217
I O
OH
Me 262
BTHF, 0 °C to RT, THF
I
OH
Me 263
94 218
HO2CCl
Cl
CF3 264
BTHF, THF,RT
Cl
Cl
CF3
HO
265
75 219
O
O
O OHO
266
BMS, (MeO)3B, RT
O
O
O OH 267
85
220
OO
OHO
268
BMS, THF, RT OOHO
269
83 221
98
N
OO
COOEtHOOC
270
BMS, EtOH,-20 °C to RT
N
OO
COOEtHO
271
70 222
O OO
OH 272
BMS, THF, RT O O
OH 273
74 223
COOHO OMe
274
BMS, THF, RT
OO 275
78 224
HOOH
O
OBr
276
BMS, THF,-20 °C to RT HO
OH
Br
277
95 225
O OR'
HOOC SPh 278
BMS, THF, -10 °C
O OR'
SPhHO
279
88 226
O
O
O2N
O
HO
280
BMS, 0 °C to RT O
O
O2NHO
281
100 227
HOOC OO
NpβNp-naphthalene
282
BMS, THF, RT HOH2C
OO
Npβ 283
84 228
S
O OH
O O 284
1.BMS (1.2 equiv.)CH2Cl2,
37 °C, 1.5h
2.KF, (aq.50 wt %,37 °C, 45 min)
S
OH
O O 285
86 214a
COOCH3
COOH 286
NaBH4, I2, THF,0 °C
COOCH3
OH 287
82 229
Table 3.1 (Continued)
99
3.2.2 Reduction involving ester and lactone carbony ls
Esters and lactones are reduced to alcohols or diols by reagents like
LiAlH4, BMS, and NaBH4 etc. These classes of molecules can be partially reduced
to aldehydes with the participation of a single hydride. Starting from esters,
aldehydes are formed via the corresponding hemiacetals. Starting from lactones,
the products are generally lactols 211(Table 3.2, No. 312 and 314).
Reduction of the ester carbonyls with borane complexes generally
requires refluxing conditions to effectively push the reduction to completion.
Several examples are available on the use of BTHF or BMS for the reduction of
ester carbonyls. When BMS is used, the dimethyl sulfide is usually distilled from
the refluxing solution to drive the reduction to completion.203 At elevated
temperatures, BTHF can cleave the tetrahydrofuran ring233 (298), producing butyl
O
OMe
OOH 288
BMS, THF,0 °C O
OMe
OH 289
100 230
F3C NH2
OHO
290
1.LiBH4, (2min THF, 3.2 equiv)
TMSCl (6.4 equiv.)THF, 0 °C
to RT
2.MeOH, 0 °C
3.1 M aq.NaOH, 0 °C to RT
F3C NH2
HO
291
96 231
COOCH3
COOH 292
BMS, THF,
-10°C to 20 °C O
O
293
54 232
COOCH3
COOH 294
ClCO2Et, NaBH4, MeOH, 5 °C
O
O
295
37 232
COOH
COOCH3 296
BMS, THF,
-10°C to 20 °C O
O 297
55 232
Table 3.1 (Continued)
100
borate (299) and thus decreasing the amount of borane available for the desired
reduction (Figure 3.2). Table 3.2 shows examples of reduction of ester carbonyls
in the presence of other reducible groups.
O BH3 BO
O O
298 299
Figure 3.2 Formation of butyl borate from BTHF
Table 3.2 Reduction of ester carbonyls using boran e reagents
Starting material Reagents and
conditions Product Yield References
OO HCO2C2H5
300
NaBH4, EtOH, reflux
OO HOH
301 88 234
NH N
HNH
OBz
O
BzO
CO2Me MeO2C
O
302
BMS, reflux NH N
HNH
OBz
O
BzO
O
HO OH
303
85 235
N
HN
BOC
CO2MeOAc
BnO
304
BMS, reflux N
HN
BOC
CH3OH
BnO
305
48 236
NOPMB
CO2Et
306
LiBH4,EtOH-THF, RT
NOPMB
OH
307
95 237
O
O
OHCO2Me
CO2MeAr
308
LiTEBH, THF, -78 °C
O
O
OH
CO2MeAr
OH
309
87 238
N
S
O
O NEt
310
LiTEBH, THF, 0 °C
N
S
HO N
311
66 239
101
N
O O
Ph F
312
LiTSBBH,-75 °C
CF3
CF3O
Cl
N
O O
O
F
CF3
CF3
313
70 240
NO
O O
Bn
314
I. Li(s-Bu)3BH (1 M in THF, 1.03 equiv), THF, -15- 5 °C, 2 h
2. aq.NaOH, -5 °C
3. aq.H2O2 (30 wt %), < 20 °C, 1 h
4. solid NaHSO3, 10 °C, 30 min.
NO
HO O
Bn
315
80 241
O
NOMe
O
MePh
316
LiBH4, 1.5 equiv. THF, -15 °C to
RT
OH
NOMe
MePh
OH
317
95 242
MeOOMe
O
OOH
318
BMS (1.02 equiv), NaBH4,
THF, 12-16 °C, 1 h
HOOMe
OOH
319
89 243
OMeOMe
O
O
HO
RO
320
BMS, NaBH4, THF, RT
OMeOH
O
HO
RO
321
80 244
OEtOEt
O
O
HO
N3
322
BMS, NaBH4, THF, RT
OEtOH
O
HO
N3
323
75 245
R1
R1
OH O
O
OMeOMe
R2
R3
R2
324
NaBH4,DMF,RT
R1
R1
OH
R2
R3
R2
O
O
325
88 246
COOCH3p-Tol
COOH
326
BMS, THF, 0 °C
CH2OHp-Tol
COOH 327
85 247
Table 3.2 (Continued)
102
3.2.3 Reduction of carbonyls of amides / imides
Amides can be selectively reduced to alcohols or amines with alkali metal
trialkyl borohydride reagents such as lithium triethylborohydride and lithium
dialkylaminoborohydrides. The attack of the amide carbonyl group by a hydride
occurs through a tetracoordinated intermediate, which can proceed either by
breaking of the C-N bond or by breaking of the C-O bond resulting in the
formation of aldehyde or amine respectively. The reactivity of amide carbonyl with
other carbonyl groups can be differentiated by their action with some of the
specific reducing agents. Few examples are listed in the Table 3.3
Table 3.3 Reduction of amide/ imide carbonyls usin g borane reagents
Starting material Reagents
and conditions
Product Yield References
NHHN
OHNPh
Ph
328
LiTEBH, THF, 20 °C
NHHN
Ph
HO
329
66 248
Ar NPh
O
330
LiNH2BH3, THF, RT
Ar OH
331
66 249
NPh
O
O
O2N
H
H
H
332
BTHF, THF, reflux
NPh
O2N
H
H
H
333
90 250
OO
N
O
O
Ph
334
BMS, THF, MeOH, HC,
0-5 °C
OO
N Ph
HCl
335
80 251
NH
H3COO Cl
336
BTHF, reflux
NH
H3COCl
337
252
103
HN
NH
MeOOMe
O
O
338
BTHF, THF, reflux
HN
NH
MeOOMe
339
80 253
NN
PhthNO
O
CO2t-Bu
340
BTHF, THF, reflux N
NPhthN
O CO2t-Bu
341
Yield not given
254
O
HN
O Ph
342
BTHF, aq.HCl, reflux
O
HN
Ph
HCl
343
82 255
HNOH
Cl
Cl
O
O
344
BTHF, THF, 66 °C
HNOH
Cl
Cl
345
84 256
NH
O
O
RO
ClCl
346
BMS, THF,reflux
NH
RO
ClCl
347
86 257
HN
NH2
O2NNH2
O
348
BTHF (7 equiv.),
THF
HN
NH2
O2NNH2
349
85 258
NOCO2CH3
CO2Et
OO
350
BMS, THF, RT
N
CO2CH3
CO2Et
OO
351
40 259
Table 3.3 (Continued)
104
350
1.DIBAL-H
2.TsOH, MeOH
NMeOCO2C(CH3)2
CO2Et
OO
352
86 259
NOCO2C(CH3)3
NCCO2Et
353
LiEt3BH, THF, -78°C
NCO2C(CH3)2
NCCO2Et
HO
354
78 260
O
NO O
PMB
355
BMS,(3 equi,)THF, 24 h, RT
O
NO
PMB
356
58 261
3.2.4 Reduction of carbonyls of anhydrides
Cyclic anhydrides are useful precursors for lactones using reduction
reactions262,265 (Table 3.4 No. 357, 360 and 365). The reduction of unsymmetrical
anhydrides is regioselective and appears to be nonselective with procedure
involving zinc/acetic acid.262b Hydride attack takes place on the carbonyl group
that is vicinal to the most substituted carbon.
Selectrides are conveniently used for the regioselective reduction of
anhydrides. Reaction of tri-sec-butylborane with potassium hydride or lithium
trimethoxyaluminium hydride gave potassium tri-sec-butylborohydride (and is
called K-Selectride) or lithium tri-sec-butylborohydride (and is called L-Selectride).
The potassium and Lithium derivatives are both effective for reductions, although
by analogy to other borohydrides, the lithium derivative may be somewhat
stronger. The selectivity of a given selectride reagent can be influenced by the
addition of metal salts like MgBr2 or ZnI2.262 Table 3.4 shows few examples for
the reduction of carbonyls of anhydrides using unconventional borane reagents.
Table 3.3 (Continued)
105
Table 3.4 Reduction of carbonyls of anhydrides usin g unconventional borane reagents
Starting material Reagents
and conditions
Product Yield References
O
OMe O
O
357
L-Selectride, RT
O
OMe O
+ 358
O
OMe
O 359
90:10
262
O
O
O 360
K-Selectride, RT O
O
O
O
+
361 & 362
19:1 263
O
O OMeO2C CO2Me
363
BER-Ni(OAc)2, RT
OHCO2Me
364
85 264
OO
O
365
NaBH4, DMF,0-20 °C,
O
O
366
55 265
X
HN
O O
O O
367
NaBH4,THF, MeOH,reflux X
HN
OH
368
91 266
3.3 Effect of Solvent on the Selective Reduction of Esters Using Sodium borohydride and Methanol
The introduction of various metal hydrides namely sodium borohydride
(NaBH4) lithium aluminum hydride (LAH) and Lithium borohydride have been
played important roles in the history of reduction of organic functional groups.267
Sodium borohydride, since its discovery by Schlesinger,268 Brown and co-
workers, is one of the most easily available among many complex metal
hydrides. It is easier to manipulate than lithium aluminium hydride or lithium
borohydride because of its lower sensitivity towards moisture. LAH is a poor
selective reducing agent because of its excessive reducing ability. It is very well
106
established that the reducing capacity of the borohydride is markedly affected by
changing the metal ion.267
Thus sodium borohydride reduces typical esters such as ethyl acetate and
ethyl benzoate in methanol and THF at refluxing temperature. However, the
reducing properties of sodium borohydride could be amplified by (a) varying the
solvent, (b) changing the cation, (c) the use of catalysts and (d) the presence of
activating substituent.269 It is known that LiBH4 reduces esters very easily. In
aqueous solutions, there is no measurable difference in the rate constants for the
reactions of sodium and lithium borohydrides. However in isopropyl alcohol the
rate constant for LiBH4 is several times greater than that of sodium salt. This
suggests that the enhancing effect of lithium ions will be the greatest in solvents
of the low dielectric constants.269 The reduction of esters by diborane, BTHF, or
by BMS is relatively slow. Accordingly, LiAlH4, LiBH4 or Ca(BH4)2 have been the
preferred reagents for such reductions. Calcium, strontium and barium
borohydrides are reducing agents of higher reducing activity than the
borohydrides of sodium, potassium and lithium. This may be ascribed perhaps to
the more covalent character of these compounds. However, the selectivity in
reducing properties of calcium borohydride resembles the selectivity of sodium
borohydride.269
As discussed above, sodium borohydride, either by itself 270 or in
combination with other reagents has been employed for a wide range of the
reduction of esters to alcohols. Heating or use of poly ethylene glycol of high
boiling point or metal salt additives is often required since esters are less reactive
than aldehydes or ketones.
Preferred solvents for the reductions using sodium borohydride include
alcohols (MeOH, EtOH), THF and 2-MeTHF but examples in NMP271 and DME272
also exist. After the completion of the reaction, aqueous acidic or basic quenches
consume residual borohydride. Alternatively, acetone can be added to consume
excess NaBH4 prior to the aqueous quench.
Thus the enhanced reactivity of sodium borohydride in protic solvents can
be utilized for the reduction of esters. At 60 °C a solution of sodium borohydride
in methanol rapidly releases 4 moles of hydrogen. Presumably, the reaction
107
involved loss of hydride, forming sodium alkoxyborohydrides, which are capable
of reducing esters.273 When methanol reacts with sodium borohydride the
reduction was implied to involve various alkoxyhydroborate, such as BH3(OMe)-,
BH2(OMe)2-, BH(OMe)3
-.274 These species or their aggregated forms acted as
Lewis acid and show higher reducing power than sodium borohydride and thus
facilitated the reduction of esters. In fact, it was previously reported that B(OCH3)3
catalyzed the reduction of esters by sodium borohydride in ether at 25 °C.
The effect of solvents and metal ion for the reduction of ketones and
esters using sodium borohydride have been well documented.273 Soai et al.
reported the effect of solvents on the reduction of esters using sodium
borohydride which is known to be incapable of reducing such functionalities.275 In
mixed solvents like t- butyl alcohol-methanol or THF- MeOH, various carboxylic
esters and lactones were found to be reduced by sodium borohydride to the
corresponding alcohols, diols or polyols in high yields. Table 3.5 shows examples
of reduction of ester carbonyls with NaBH4 and MeOH.
108
Table 3.5 Reduction of ester carbonyls using NaBH 4 and MeOH
Starting material Reagents and
conditions Product Yield References
CO2Me
369
NaBH4,MeOH, THF, 70 °C, 2-4 h
OH
370
90 276
COOEtBoc-N
Ph
371
NaBH4,MeOH, THF, 50-55 °C Boc-N
Ph
OH
372
88 275
N
O
OMe
373
NaBH4,MeOH, THF, 70 °C N
OH
374
95 275,276
NO
t-BuOS
N
O
O
O
375
NaBH4 (2 equiv.), MeOH (4 equiv),
NaB(OAc)3H , THF, 25 °C
NO
t-BuOS
NOH
O
376
89 277
N CO2R
Cl
377
NaBH4,MeOH, THF, 70 °C, 1 h N
Cl
OH
378
93 278
O CO2Me
379
NaBH4,MeOH, THF, 70 °C, 2 h
OOH
380 56 278
N
COOCH3
381
NaBH4,MeOH, THF, 70 °C
N
OH
382
91 276
109
3.4 Results and Discussion
It has been seen that boron based reagents are widely used for the
selective reduction of a number of functional groups. Hence, attempts have been
made for the chemical and conditional modification of borane reagents such as
BMS and NaBH4, for the efficient selective reduction of carbonyls derived from
hydroxy acids. This has been carried out to modify (2S,3S) and (2S,3R)-
tetrahydro-3-hydroxy-5-oxo-2, 3- furan dicarboxylic acids (6 and 7) to desired
structures to accomplish the synthesis of useful enantiomerically pure
compounds (Figure 3.3) as boron based reagents are the most appropriate
reagents for cumulating mostly the reduction reactions. Even though many
reductions with borohydrides are selective and specific, borohydrides have
limited use when the substrates contains polar groups, such as –OH groups.279
However, a careful use of these reagents, in catalytic or stoichiometric conditions,
with appropriate solvents or metal ions, can impart amplification of their ability to
discriminate between reducible functional groups.269
O
OO
OHO
H
O
OO
HO
H O
OO
OH
HOH
COOCH3
O
OO
OO
H
OOO H
CH2OHOH
CH2OH
OO
OH
CH2OH
OHH
CH2OH
N R
O
O
HHO
HO
OO HN
OH
OH
O
OO
OH
RR=H,CH3
HOOHOH
HOOH
OOH
OHHO
HN
OHHOHO
OO HCOOH
R'R
6. R=COOH, R'=OH7.R=OH, R'=COOH
209
208
210
212
231
383
384
385
386
387
388
389
Figure 3.3 Enantiomerically pure γγγγ-butyrolactone based intermediates derived from 6 and 7
110
The carboxylic acid group is reduced selectively in presence of an ester
group by BTHF or BMS.280 Even though the reduction of a carboxylic acid group
in presence of an ester or a lactone is possible, the selective reduction of an
ester group in presence of a lactone is more challenging and only few reports
are available.227,281 Borohydrides also have been used as catalysts to expedite
reductions using BTHF and BMS reagents.244,245
For instance, epoxide can be reduced282 with BTHF complex much faster
in the presence of catalytic amount of NaBH4 or LiBH4. Borane coordinates to the
epoxide enhances the polarization of its C-O bond resulting in facile delivery of
hydride from added borate anion to the carbon concerned. One mole of hydride per
mole of compound is utilized; hydrogen is not evolved, and observed a predominant
anti-Markovnikov opening of the epoxide ring (Scheme 3.2). The use of higher
concentrations of the more soluble lithium borohydride gives faster reaction with
similar products.
OBH3
NaBH4catalyst
OH
+OH
26% 74%390 391 392
Scheme 3.2 Reduction of epoxide with BTHF
Saito and co-workers effectively extended the similar catalytic activity of
borohydrides for the selective reduction of α-hydroxy ester group of molecules
such as malate and tartarate diesters, using BMS and 5 mol% of catalytic NaBH4,
(Table 3.2 No.318-323) which in turn provides versatile chiral building blocks in
synthesis.244,245
Selective reduction using BMS and catalytic amount of sodium
borohydride, ester carbonyl of α-hydroxy esters in presence of azide group is
also demonstrated.244,245 Apparently, substituted benzene directed regio-selective
reduction of esters using BMS proceeds even without catalyst.283 Also phthalides
have been converted to the corresponding naphthalenic lignan lactones by the
selective reduction of the carbonyl group just using NaBH4 in DMF.246 In this
reduction, the ester carbonyl group adjacent to OH was reduced (Table 3.2,
No.324 & 325)
111
Saito and co-workers explained the mechanism of the selective reduction
using malic and tartaric diesters. When diethyl (S)-malate (DEM, 393) was
treated with one-mole equivalent borane dimethyl sulphide in dry tetrahydrofuran
at room temperature, evolution of hydrogen gas was observed immediately and
ceased after 45 minutes.The amount of which was equivalent to a molar quantity
of the diethyl malate employed (Scheme 3.3). The authors claimed that diagnosis
by TLC at this stage indicated that no reduction had proceeded yet, only one spot
corresponding to the starting diethyl malate being visualized. The authors
suggest that the initial product should be oxyborane – type intermediate (395)
(Figure 3.4). After sodium borohydride (5 mol %) was added to the reaction
mixture, immediate TLC monitoring indicated that reduction actually started and
required one hour at room temperature for completion followed by EtOH addition
for quenching the reduction. The authors also claimed that only a small amount of
hydrogen gas evolved on this operation, which probably means that nearly all the
hydrogen of the boron atoms were consumed for the reduction.
EtO2CCO2Et
OH
393
Cat.NaBH4
CO2EtHO
HO
major
51
EtOOCOH
HO
+minor
394
BMS, THF
Scheme 3.3 Selective reduction of DEM using BMS and catalytic amount of NaBH 4
The regio-selectivity of the reduction of malic diesters, using borane
dimethyl sulphide and catalytic amount of sodium borohydride, is controlled by
the steric factors of the ester groups. Dimethyl malate gives a mixture of products
in the ratio from 80:20 to 60:40. More sterically demanding diethyl or diisopropyl
malate gives better regio-selectivity.
Saito and co-workers proposed two possible transition states 396 (five
membered) and 397 (six membered) for the reduction of malic diesters (Figure
3.4). Neighboring group participation is most favored for five membered transition
state.244 In addition, severe 1, 3 diaxial interactions between the ester alkoxy-
group and the hydrogen on the boron atom destabilize 397 which in turn explains
the selectivity observed in the reduction of malic diesters.
112
CO2ROB
O
H H
RORO2C OR
O OB
H H
396 397
RO2CCO2R
OBH2
395
Figure 3.4 Transition state structures of DEM
In the case of diethyl (R, R)-tartrate, another acyclic hydroxy ester, the
authors proposed two possible transition states 398 and 399 (Figure 3.5) for the
site selective reduction using BMS and catalytic amount of sodium borohydride.
OR
OBO
HH
Z
O
RO2C ORZ
OB
O
H H
398 399
Figure 3.5 Transition state structures of DET
Though the reaction is highly potential, the experiment was limited to
only a few hydroxy esters and the mechanism proposed by Saito and co-
workers leaves few questions to be answered for generalizing the viability of the
reaction. For instance, when the reaction was performed using tartaric diesters
with protected hydroxyl groups (t-Bu or Benzyl) or in cases where the –OH
group of tartaric diester was replaced by halogens; the observed selectivity was
very poor.244
It was demonstrated that the accuracy of the selective reduction in the
case of esters of hydroxy acids namely malic and tartaric acids using BMS and
catalytic amount of NaBH4 at room temperature and tentatively proposed to
proceed through an alkoxy-BH2 (RO-BH2) intermediates.244 However, no 11B NMR
spectroscopic data was available to support this proposal. Hence the 11B NMR
spectroscopic analysis is an ideal tool for revealing the actual mechanism.
In this context, attempts have been made for the reduction of the acid 6
with BTHF at room temperature to get (4R,5R)-4-hydroxy-4,5-bis(hydroxymethyl)
dihydrofuran-2(3H)-one (400). However, repeated attempts for the reduction
under this condition failed to proceed in the expected line (Scheme 3.4).
However, the 11B NMR spectroscopy analysis of the commercial BTHF sample
113
indicates the unavailability of any B-H bonds, as the reagent might have
decomposed during shipping to tropical places in this case.
O H
OH
O OH
OH6
400
BTHF
Scheme 3.4 Reduction of 6 using BTHF
Reductions using BMS and NaBH4-I2 combination results in the formation
of insoluble polymeric intermediates which eventually inhibits the completion of
the reduction reaction. The laxity of the reaction could also be due to the
formation of stable acyloxy borane complexes (401) (Scheme 3.5).
O HCO2H
O"BH 3"
OB
O
O H6
401 Scheme 3.5 (Acyloxy)borane complex of 6
Since the direct reduction of 6 gave intractable product, attention has been
focused on the reduction of dimethyl and diisopropyl esters of 6 and 7 (Figure
3.6), using BMS and catalytic amount of sodium borohydride, developed by Saito
and co-workers.
OO H
COOROH
COOR153.R=-CH3155.R=-CH(CH3)2
OO H
COOROH
COOR158.R=-CH3160.R=-CH(CH3)2
Figure 3.6 Diesters of 6 and 7
In this context, for getting insight into the mechanism and to find out the
intermediate involved in the site selective reduction of α-hydroxy esters,
diastereomeric esters of garcinia and hibiscus acids (153, 155, 158 and 160,
(which in turn are derivatives of tartaric acids) are appropriate molecules for
further exploration of the site selectivity observed (Figure 3.7).
114
RO2CCO2R
OH
RO2C
HO O HCO2R
OHCO2R
O HCO2R
OHCO2R
Dialkyl malate Dialkyl tartarate Diesters of 6 & 7
O OOH
CO2R
Figure 3.7 Diesters of αααα-hydroxy acids
This chapter describes the results of the studies on the site selective,
partial and tandem reductions of esters of 6 and 7 and representative α-hydroxy
esters using conditionally modified BMS and NaBH4 reagents (Scheme 3.6).
OO
H
COOR
COOROH
6.R=-H153.R=-CH3, 155.R=CH(CH3)2
BMS/Cat.NaBH 4
OO
H
COOR
OHOH
NaBH4/MeOHHOOH
HO
H
OH
HO
THF, 0 C0 C
D
26 = + 72.78, (C = 0.143, Acetone ) mp, 55-60 oC
OO
H
COOR
O
H
1.BMS/THF2.MeOH, 0 C
OO
H
COOR
OHOH
BMS/Cat.NaOMeTHF, 0 C
D
26 = + 2.75, (C = 0.40,MeOH)
HO
204.R=-CH3406.R=-CH(CH3)2
αα
°
°
°
°
204.R=-CH3406.R=-CH(CH3)2
386
414
Scheme 3.6 Reduction of esters of 6 with (i) BMS an d catalytic amount of NaBH4 and
(ii) NaBH 4/MeOH at 0 °°°°C
3.4.1 Site selective reduction of dialkyl ( 2S, 3S)-tetrahydro-3-hydroxy -5-oxo-2, 3-furandicarboxylates (153 and 155) using BM S and catalytic amount of NaBH 4
To carry out the site selective reduction of α-hydroxy esters having
multiple carboxylic esters, using the combination of BMS and catalytic amount of
sodium borohydride in anhydrous tetrahydrofuran (THF), the dialkyl (2S, 3S) and
(2S, 3R)–tetrahydro-3-hydroxy -5-oxo-2, 3-furandicarboxylates (153,155,158
115
&160) (Figure 3.4) were selected. The progress of the reaction was continued by 11B NMR analysis of aliquots withdrawn periodically from the reaction mixture.
When dimethyl (2S, 3S)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylate
(153) was treated with one mole equivalent of BMS in THF, at 0 °C (Scheme 3.7),
one equivalent of hydrogen gas evolved instantaneously and was measured by
gas buret technique (Figure 3.8).284 After the gas evolution, an aliquot of the
reaction mixture was analyzed by 11B NMR spectroscopy and observed the
complete consumption of BMS at 25 °C (Figure 3.11). The 11B NMR spectrum of
the reaction mixture displayed broad singlets at + 22 ppm attributable to
polymeric trialkoxyboranes, similar to Pin3B2.285 There observed no signals which
attributed to an intermediate corresponding to alkoxy-BH2, such as 402 (Figure
3.9). Addition of catalytic amount of NaBH4 failed to cause any significant change
in the 11B NMR spectrum except that the trialkoxyborane signal at +22 intensified
(Figure 3.12). When the reaction is quenched with MeOH after 3 h, very little
hydrogen was evolved and the predominant signal in the 11B NMR spectrum of
the reaction mixture was attributable to trimethoxyborane B(OMe)3 (δ +18 ppm).
A minor peak at +10 ppm, due to tetraalkoxyborate ion, was also visible in the
spectrum (Figure 3.13). Workup of the reaction mixture furnished the isolation of
methyl (2S,3R)-terahydro-3-hydroxy-3-hydroxymethyl-5-oxo-furan-2-carboxylate
(204) and methyl (2R,3S)-tetrahydro-3-hydroxy-2-(hydroxymethyl)-5-oxo-furan-3-
carboxylate (403) indicative of the reduction of the C2 and C3-carbonyl groups in
a ratio of 70:30.
The structure of 204 was confirmed on the basis of IR, 1H, 13C NMR and
mass spectra. The IR spectrum displayed absorption bands at 3416 cm-1
(presence of -OH group), at 1771 cm-1 (presence of lactone carbonyl) and at
1735 cm-1 (the presence of ester carbonyl). The 1H NMR spectrum displayed
signals at δ 4.5 - 4.24 (AB quartet; corresponds to the methylene protons), at δ
3.02-2.47 (AB quartet; due to methylene protons in the lactone ring), at δ 4.44
(singlet; corresponds to methine proton) and at δ 3.76 (singlet; corresponds to -
OCH3 protons). The 13C NMR spectrum displayed nine different signals at
174.776, 167.826, 105.161, 97.307, 79.196, 77.426, 76.326, 49.6 and 37.556 which
confirmed the structure of 204 (Figure 3.14a-d).
116
Figure 3.8 Gas burette apparatus
OO CO2R
CO2R
OBH2
402
Figure 3.9 Oxyborane intermediate of 153 with BMS
OO HCOOCH3
HO OH+
OO H
HO COOCH3
OHBMS/THF
NaBH4 (5 mol%)153
204 40370:30
Scheme 3.7 Selective reduction of 153 using BMS and catalytic amount of NaBH 4
117
Figure 3.10 11B NMR spectrum of solution of 153 immediately after the addition of BMS
Figure 3.11 11B NMR spectrum of a mixture of 153 and BMS after th e gas evolution
118
Figure 3.12 11B NMR spectrum of a mixture of 153 and BMS after th e addition of Sodiumborohydride
Figure 3.13 11B NMR spectrum of a mixture of 153, BMS and NaBH 4 after quenching with MeOH
119
IR (liquid film)
OO HCOOCH3OH
OH204
Figure 3.14a
1H NMR, 400 MHz, Solvent : Acetone-d6
OO HCOOCH3OH
OH204
Figure 3.14b
120
The structure of 204 was further confirmed by the preparation of chloral 286(dioxolane) derivative namely methyl (5R, 6S) 8-oxo-2-trichloromethyl-1,3,7-
trioxa-spiro[4.4]nonane-6-carboxylate (404) and acetyl derivative namely methyl
(2S, 3R)-terahydro-3-acetyloxy-3-acetyloxymethyl-5-oxo-furan-2-carboxylate
(405) (Scheme 3.8)
3.4.2 Conversion of methyl (2 S, 3R)-terahydro-3-hydroxy-3-hydroxymethyl-5-oxo-furan-2 carboxylate (204) to methyl (5 R, 6S) 8-oxo-2-trichloromethyl-1,3,7-trioxaspiro[4.4]nonane-6-carb oxylate (404)
Treatment of 204 with anhydrous trichloroacetaldehyde in presence of con.
H2SO4 gave methyl (5R, 6S) 8-oxo-2-trichloromethyl-1,3,7-trioxaspiro[4.4]nonane-6-
carboxylate as a diastereomeric mixture (Scheme 3.9). Purification and
recrystallisation (diethyl ether:hexane) resulted in the isolation of 404 as a solid
(mp, 162 –164 °C) in 89% yield, 29D][α +13.14, (c 0.25, CHCl3) (Scheme 3.5).
Structure was confirmed on the basis of IR, 1H, 13C NMR and mass spectra. The IR
spectrum exhibited the characteristic absorption bands at 1824, 1747, 1712 cm-1
13C NMR 100 MHz, Solvent : Acetone-d6
OO HCOOCH3OH
OH204
Figure 3.14c
OO HCOOCH3OH
OH204
Figure 3.14d
121
(due to carbonyl stretching frequencies). The 1H NMR displayed signals at 6.0487
(singlet; due to the protons in dioxolane ring), at 4.8 (singlet; due to methine proton),
at δ 4.4762- 4.3727(AB quartet; due to methylene protons), at 3.6971 (singlet; due to
-OCH3 protons) and at 2.9686- 2.74505 (AB quartet; due to methylene protons in the
lactone ring). Nine different signals in 13C NMR spectrum at 174.776, 167.826,
105.161, 97.307, 79.196, 77.426, 76.326, 49.6 and 37.55 also confirmed the
structure of 404 (Figure 3.15a-d). Mass spectrum indicated FAB+ (M+H)+ at m/e
305.07 due to the hydrolysed compound (5R,6S)-8-oxo-2-(trichloromethyl)-1,3,7-
trioxaspiro[4.4]nonane-6-carboxylic acid.
CCl3CHO
H2SO4
OO HCOOCH3
O
OCCl3
404
204
Scheme 3.8 Preparation of 404
IR (KBr pellet)
OO HCOOCH3
O
O
CCl3
404
Figure 3.15a
122
1H NMR 300 MHz, Solvent : CDCl3
OO HCOOCH3
O
O
CCl3
404
Figure 3.15b
13C NMR 75 MHz, Solvent : CDCl3
OO HCOOCH3
O
O
CCl3
404
Figure 3.15c
123
OO HCOOCH3
O
O
CCl3
404
Figure 3.15d
3.4.3 Conversion of methyl (2 S, 3R)-terahydro-3-hydroxy-3-hydroxymethyl-5-oxo-furan-2 carboxylate (204) to methyl (2 S, 3R)-terahydro-3-acetyloxy-3-acetyloxymethyl-5-oxo- furan-2-carboxyl ate (405)
Acetyl chloride was added dropwise to 204 under stirring (continued for 12
hours). It is clear from the physical data that both the hydroxyl groups were
protected and methyl (2S, 3R)-terahydro-3-acetyloxy-3-acetyloxymethyl-5-oxo-
furan-2-carboxylate (405) was isolated in quantitative yield (Scheme 3.8).
204
OO OCH3
O
OCOCH3H3COCO
405
CH3COCl
Scheme 3.9 Preparation of 405
The IR spectrum displayed the characteristic absorption bands at 2969
cm-1 (characteristic of C-H stretch) and at 1780, 1748 cm-1 (shows the presence
of lactone and ester carbonyls). The 1H NMR spectrum displayed two sets of
diasterotopic hydrogens. Signals at δ 4.4 - 4.6 (AB quartet; presence of
methylene protons), at δ 2.8 - 3.2 (AB quartet; indicate the presence of methylene
protons in the lactone ring), at δ 3.9 (singlet; corresponds to -OCH3 protons) and
at 2.2 (singlet; corresponds to –OCOCH3 protons) confirmed the number of
protons in the molecule. The 13C spectrum displayed 11 different signals at δ
124
172.16, 169.8, 169.6, 167.02, 83.82, 80. 66, 61.59, 53.09, 37.66, 21.49 and 20.38
which confirmed the number of carbon atoms of the molecule (Figure 3.16a-d).
IR (liquid film)
OO OCH3
O
OCOCH3H3COCO
405
Figure 3.16a
1H NMR 300 MHz, Solvent : CDCl3
OO OCH3
O
OCOCH3H3COCO
405
Figure 3.16b
125
13C NMR 75 MHz, Solvent : CDCl3
OO OCH3
O
OCOCH3H3COCO
405
Figure 3.16c
OO OCH3
O
OCOCH3H3COCO
405
Figure 3.16d
The diisopropyl (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylate
(155) was also reduced in the same way as that of 153 (Scheme 3.10) using
BMS and catalytic amount of NaBH4. The progress of the reaction was monitored
by recording the 11B NMR spectrum and is found to be similar as that of 153.
After the gas evolution, an aliquot of the reaction mixture was analyzed by 11B
NMR spectroscopy and observed that all the BMS was consumed and the 11B
NMR does not show any peak corresponds to unreacted BMS at 25 °C. The
reaction mixture displayed broad singlets at + 22 ppm and +28 ppm attributable
to polymeric trialkoxyboranes, similar to Pin3B2 and dialkoxyborane respectively
(Figure 3.18). There were no signals attributable to an intermediate
corresponding to alkoxy-BH2, such as 402. Addition of catalytic amount of NaBH4
126
did not show any significant change in the 11B NMR spectrum except that the
dialkoxyborane signal at +28 ppm disappeared and the trialkoxyborae signal at
+22 intensified (Figure 3.19). When the reaction is quenched with MeOH after 3
h, very little was hydrogen evolved and the predominant signal in the 11B NMR
spectrum of the reaction mixture was attributable to trimethoxyborane B(OMe)3 (δ
+19 ppm). A minor peak at +10 ppm, due to tetraalkoxyborate ion, was also
visible in the spectrum (Figure 3.20). Workup of the reaction mixture gave the C2
and C3-carbonyl reduced isopropyl (2S,3R)-tetrahydro-3-hydroxy-3-(hydroxymethyl)-
5-oxo-furan-2-carboxylate (406) and Isopropyl (2R,3S)- tetrahydro-3-hydroxy-2-
(hydroxymethyl)-5-oxo-furan-3-carboxylate (407). However, the site selectivity
has turned out to be 90:10 as verified by TLC analysis. The subsequent
chromatographic purification of the reaction mixture over silica gel (60-120 mesh,
ethyl acetate–hexane 7:3) afforded the isopropyl (2S,3R)-tetrahydro-3-hydroxy-3-
(hydroxymethyl)-5-oxo-furan-2-carboxylate (406) as major product in 80% yield
as a crystalline solid. Mp 55-60 °C, 26D][α +72.78 (c 0.143, Acetone). Structure
was confirmed on the basis of IR, 1H, 13C NMR and mass spectra.
The IR absorption spectrum displayed peaks at 3443 cm-1 (indicating the
presence of –OH groups), at 1776.39, 1730 cm-1 (due to the lactone and ester
carbonyls). The 1H NMR displayed signals at δ 5.151 (singlet; due to the methine
proton in isopropyl group), at 4.75 (singlet; due to methine proton in lactone ring),
at δ 4.4- 4.3 (AB quartet; corresponds to methylene protons on CH2O group), at δ
2.8-2.6 (AB quartet; corresponds to the methylene protons in the lactone ring)
and at δ 1.3 (doublet; due to protons in methyl groups). The 13C NMR displayed
nine different signals at δ 174.80, 170.79, 78.08, 76.70, 74.02, 71.64, 38.93,
21.75 and 21.73 also confirmed the number of carbon atoms of the molecule
(Figure 3.23a-e). The DEPT 135 shows two -ve signals at δ 74 and 38
corresponds to CH2 carbon atoms. The HRMS (ES+) calculated for C9H14O6Na:
241.0688, Found: 241.0686 (Figure 3.21)
127
BMS/THFOO
OH
O
O
HO
406
155
OO
O
O
OH
HO+
90:10
407
NaBH4, 0 C°
Scheme 3.10 Selective reduction of 155 using BMS an d catalytic amount of NaBH 4
Figure 3.17 11B NMR spectrum of solution of 155 immediately after the addition of
BMS
Figure 3.18 11B NMR spectrum of a mixture of 155 and BMS after th e gas evolution
128
Figure 3.19 11B NMR spectrum of a mixture of 155 and BMS after th e addition of sodiumborohydride
Figure 3.20 11B NMR spectrum of a mixture of 155, BMS and NaBH 4 after quenching with MeOH
Figure 3.21 Single mass analysis of 406
129
IR (KBr pellet)
OO O
O
OHO
O155
Figure 3.22a
1H NMR 400 MHz, Solvent : CDCl3
OO O
O
OHO
O155
Figure 3.22b
13C NMR 100 MHz, Solvent : CDCl3
OO O
O
OHO
O155
Figure 3.22c
130
OO O
O
OHO
O155
Figure 3.22d
IR (KBr pellet)
OO O
O
OHHO
406
Figure 3.23a
1H NMR 400 MHz, Solvent : CDCl3
OO O
O
OHHO
406
Figure 3.23b
131
13C NMR 100 MHz, Solvent : CDCl3
OO O
O
OHHO
406
Figure 3.23c
DEPT 135
OO O
O
OHHO
406
Figure 3.23d
OO O
O
OHHO
406
Figure 3.23e
132
The regioselective reduction of the C3 carboxylate group in 153 and 155 is
sensitive to the steric-requirement of the ester groups. The ester 153 gave a
mixture of products arising from the reduction of both proximal and distal ester
groups in a ratio ranging from 70:30 to 60:40. An improved site-selectivity (90:10)
was observed in the case of 155.
Also Saito and co-workers pointed out that the oxyborane intermediate is
more stable in toluene when compared to THF. To observe the formation of
oxyborane intermediate, the selective reduction of 155 was also carried out in
toluene in place of THF and the progress of the reaction was monitored by
recording the 11B NMR spectra. When 155 was treated with one mole
equivalent of BMS in toluene at 0 °C, the evolution of gas was likewise, and the 11B NMR spectra of the supernatant liquid displayed similar results as in the
conditions described above. Upon addition of NaBH4, the spectrum shows only
the formation of trialkoxyboranes. When the reaction is quenched with MeOH
the predominant signal in the 11B NMR spectrum is attributable to
trialkoxyborane (Figure 3.24-3.26).
Figure 3.24 11B NMR spectrum of a solution of 155 in toluene imme diately after the addition of BMS
133
Figure 3.25 11B NMR spectrum of a mixture of 155 and BMS after th e gas evolution
Figure 3.26 11B NMR spectrum of a mixture of 155, BMS and NaBH 4 after quenching
with MeOH
3.4.4 Mechanism of the site selective reduction of dialkyl ( 2S, 3S)- tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylates (153 and 155) using BMS and catalytic amount of NaBH 4
It is observed that one equivalent of hydrogen was evolved when BMS
was added to an equimolar amount of the ester 153 or 155 in THF at 0 °C. This is
indicative of the fact that the carbonyls of the hydroxy esters reacted with BMS in
a 1:1 stoichiometry to give alkoxy-BH2 (ROBH2) (402) type intermediates or the
reaction proceeds through a 3:1 stoichiometry to give an intermediate (408)
(Figure 3.27). The 3:1 stoichiometry will leave 66% of the BMS unreacted after
the initial reaction. However, the 11B NMR spectrum of an aliquot of the reaction
mixture after the gas evolution did not show any significant signal due to
unreacted BMS or due to the ROBH2 type intermediates. Apparently, esters 153
and 155 reacted with BMS in a 1:1 fashion and the initially formed ROBH2 type
134
intermediates quickly transfered a hydride to the proximal ester carbonyl to give a
dialkoxyborane intermediate (409) that was visible in the 11B NMR spectrum
(Figure 3.27).
OO CO2R
OB
O
H
HOR
409
OO CO2R
CO2R
O B3
408
Figure 3.27
Hetero atom containing dihydrido compound such as BH2X.L (X= -Cl,
Br,I,PR2, NR2) has been described in the literature.287 However, RO-BH2 type
compounds are usually known as transient species and tend to undergo
disproportionation to (RO)2BH and B(OR)3 compounds. Several recent reports
indicated the formation of a free RO-BH2 or complexed to carbonyl groups in the
reduction of α-hydroxy esters using BMS or BMS-NaBH4 reagents. It intrigued us
that such RO-BH2 species were not detected in the reduction of esters 153 and
155 as evidenced by 11B NMR spectral analysis.
Consequently it was decided to undertake a 11B NMR spectroscopic study
for understanding the regioselective reduction of diethyl (S)-malate (DEM) and
diethyl (R, R)-tartarate (DET) using BMS and catalytic amount of sodium
borohydride in THF and toluene independently, under the conditions described
above to check for the formation of intermediates RO-BH2. The 11B NMR
spectrum of the selective reduction of DEM, displayed peaks due to BMS at δ -
21 to-18 ppm and a minor peaks at δ 27 and 28 ppm immediately after the
addition of BMS at 0 °C (Figure 3.28). After the gas evolution, an aliquot of the
reaction mixture was analyzed by 11B NMR spectroscopy and observed that all
the BMS was consumed and the 11B NMR does not show any peak corresponds
to unreacted BMS at 25 °C (Figure 3.29). The 11B NMR spectrum of the reaction
mixture displayed broad singlets at + 22 ppm attributable to polymeric
trialkoxyboranes as described in the above reductions. There were no signals
attributable to an intermediate corresponding to alkoxy-BH2, such as 395.
Addition of catalytic amount of NaBH4 gives the polymeric trialkoxyborane and did
not show any significant change in the 11B NMR spectrum (Figure 3.30).
135
Quenching the reaction with MeOH after 3 h gave monomeric trialkoxyborane
B(OMe)3 (Figure 3.31). Reductions in THF gave similar 11B NMR data.
Figure 3.28 11B NMR spectrum of a solution of DEM immediately aft er the addition of
BMS
Figure 3.29 11B NMR spectrum of a mixture of DEM and BMS after th e gas evolution
136
Figure 3.30 11B NMR spectrum of a mixture of DEM and BMS after th e addition of sodium borohydride
Figure 3.31 11B NMR spectrum of a mixture of DEM, BMS and NaBH 4 after quenching with MeOH
The DET was also subjected to the site selective reduction using the above
procedure and the 11B NMR analysis supports the similar conclusions described in
earlier reductions (Figure 3.32-3.34).
137
Figure 3.32 11B NMR spectrum of a mixture of DET and BMS after th e gas evolution
Figure 3.33 11B NMR spectrum of a mixture of DET and BMS after th e addition of sodiumborohydride
Figure 3.34 11B NMR spectrum of a mixture of DET, BMS and NaBH 4 after quenching with MeOH
138
Again, the 11B NMR spectrum of an aliquot of the reaction mixture failed to
show any signal due to unreacted BMS or ROBH2 type intermediates. Apparently,
esters of DEM reacted with BMS in a 1:1 fashion and the initially formed ROBH2 395
type intermediates quickly transfered a hydride to the proximal ester carbonyl to give
a dialkoxyborane intermediate (410) that was visible in the 11B NMR spectrum
(Scheme 3.11). Obviously, a fast uncatalyzed hydride transfers from ROBH2 to the
proximal ester carbonyl occurs at 25 °C
EtO2CCO2Et
OBH2
395
hydride transfer CO2EtOB
O
H
HRO
Cat.NaBH4 CO2EtOB
O
OR
HH
411410
CO2EtHO
HO
major
MeOH
51
OHHO
EtO
+
O
minor
394
Scheme 3.11 Proposed mechanism of selective reducti on of DEM using BMS and catalytic amount of NaBH 4 on the basis of 11B NMR studies
Similarly, the 11B NMR spectra of 153 and 155 showed three signals
corresponding to 409, 412 and/or 413 and the polymeric form of 412. Addition of
catalytic NaBH4, resulted in the formation of the polymeric form of 412 similar to the
polymeric form of pinacol boronate esters, which exhibited broad signals in the 11B
NMR spectrum at δ+22 ppm. The intermediate 413 is expected to exhibit a singlet at
δ +19. On methanolysis, only trimethylborate is present as the boron containing
compound as evidenced by 11B NMR spectral analysis. There is a small amount of
tetramethyl borate corresponding to the catalytic amount of NaBH4 used in the
reaction. Apparently, reduction of 153 and 155 proceeds through the initial formation
of 402 and gives significant amounts of 409 and 412 even in the absence of NaBH4.
Addition of NaBH4 accelerates the formation of polymeric form of 412 (Scheme 3.12)
139
OO CO2RO
OROBH2
hydride transferOO CO2R
OB
O
H
HOR
Cat.NaBH4
OO CO2R
OB
O
OR
HH
402 409 412
R'OH
OO CO2R
OB
O
OR'
HOR
413
OO CO2RO
HHO
work up
414
OO CO2RO
ORHO
BMS
153.R=-CH3155.R=-CH(CH3)2
OO CO2R
HO OH
204.R=-CH3406.R=-CH(CH3)2
Scheme 3.12 Proposed mechanism of selective reducti on of esters of 6 using BMS and catalytic amount of NaBH 4 on the basis of 11B NMR studies
It was observed that NaOMe also catalyze the hydride transfer from the
dialkoxyborane 409 to the final alkyl (2S,3R)-tetrahydro-3-hydroxy-3-
(hydroxymethyl)-5-oxo-2 furancarboxylate (204 and 406) in BMS reduction. The 11B NMR spectroscopic study of the regioselective reduction of 155, using BMS
and catalytic amount of sodium methoxide (NaOMe), instead of NaBH4, in THF
has been carried out under the same conditions described above to check for the
involvement of catalytic NaBH4 in the site selective reduction. The 11B NMR
spectrum of the aliquot of reaction mixture recorded immediately after the
addition of BMS at 0°C which displayed the peaks due to BMS at δ -21 to-18 ppm
and a minor peaks at 9 ppm (Figure 3.35). After the gas evolution, an aliquot of
the reaction mixture was analyzed by 11B NMR spectroscopy and observed that
all the BMS was consumed and the 11B NMR did not show any peak corresponds
to unreacted BMS at 25 °C (Figure 3.36). The 11B NMR spectrum of the reaction
mixture displayed broad singlets at + 21 ppm and +27 ppm attributable to
polymeric trialkoxyboranes as described in the above reductions. There were no
signals attributable to an intermediate corresponding to alkoxy-BH2, such as 402.
Addition of catalytic amount of freshly prepared NaOMe gave the polymeric
trialkoxyborane and failed to cause any significant change in the 11B NMR
spectrum (Figure 3.37).
140
Figure 3.35 11B NMR spectrum of a solution of 155 immediately aft er the addition of BMS
Figure 3.36 11B NMR spectrum of a mixture of 155 and BMS after th e gas evolution
141
Figure 3.37 11B NMR spectrum of a mixture of 155 and BMS after th e addition of NaOMe
3.4.5 The partial reduction of propan-2-yl (2 R)-hydroxy(phenyl)ethanoate (415) using BMS
It was also observed that the dialkoxyborane initially formed during the
addition of BMS to the α-hydroxy ester could lead to the formation of a α-hydroxy
aldehyde and could be trapped as bisulfite adduct. Attempts were made for the
partial reduction of α-hydroxy esters, using BMS and subsequent quenching with
MeOH, to the α-hydroxy aldehydes.
Reports are available on bisulfite adducts which are known to give
chemical stability to the parent aldehyde and exhibit desirable physical properties
such as crystallinity, which facilitate the isolation and purification techniques.288
Hence the purification of the aldehyde via the bisulfite adduct appeared attractive
and efficient.
The propan-2-yl (2R)-hydroxy(phenyl)ethanoate (isopropyl mandelate,
415) was selected for the partial reduction using BMS in anhydrous
142
tetrahydrofuran (THF) (Scheme 3.13). The progress of the reaction was followed
by 11B NMR analysis of aliquots withdrawn periodically from the reaction mixture.
O
OHO
BMS
THF, 0 C
OR
OBO
H
MeOH
OR
OBO
R
H
OHO
415 416 417 418
SO3Na
OHHO
419
bisulfite
°
Scheme 3.13 Partial reduction of 415 using BMS
When one mole equivalent of BMS was added to a solution of 415 in THF,
at 0 °C, one equivalent of hydrogen gas evolved immediately and was measured
by gas buret technique. After the gas evolution, an aliquot of the reaction mixture
was analyzed by 11B NMR spectroscopy and observed that all the BMS was
consumed and the 11B NMR does not show any peak corresponds to unreacted
BMS at 25 °C (Figure 3.39). The 11B NMR spectrum of the reaction mixture
displayed a doublet at +28.99 ppm and clearly indicates the formation of an
aldehyde. The reaction is quenched with MeOH after 4 h, very little hydrogen
evolved and the predominant signal in the 11B NMR spectrum of the reaction
mixture was attributable to trimethoxyborane B(OMe)3 (δ +18 ppm) (Figure 3.40).
The 1H NMR analysis of the crude reaction mixture displayed a singlet at δ 9 ppm
attributable to aldehyde proton (Figure 3.42a). The reaction mixture was
concentrated under vacuum and the residue was treated with sodium bislfite
solution. However, the conversion of (2R)-hydroxy(phenyl)ethanal (418) to the
bisulfite adduct (419) was unsuccessful. Further studies for the isolation of the
aldehydes are underway.
Figure 3.38 11B NMR spectrum of a solution of 415 immediately aft er the addition of
BMS
143
Figure 3.39 11B NMR spectrum of a mixture of 415 and BMS after th e gas evolution
Figure 3.40 11B NMR spectrum of a mixture of 415 and BMS after qu enching with MeOH
144
1H NMR 400 MHz, Solvent : CDCl3
O
OHO
415
Figure 3.41a
13C NMR 400 MHz, Solvent : CDCl3
O
OHO
415
Figure 3.41b
145
1H NMR 400 MHz, Solvent : CDCl3
H
OHO
418
Figure 3.42a
3.4.6 The tandem reduction of dialkyl (2 S,3S)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylates (153 and 155) using NaBH 4 and MeOH at 0 °°°°C
The use of sodium borohydride for the simple chemoselective reductions
of aldehydes and ketones to the corresponding alcohols is well established.211
The reaction is normally carried out at reflux temperature using ethanol or
methanol as solvent. Although, theoretically, one equivalent of sodium
borohydride provides four equivalents of hydride, a slight excess of the reagent is
typically used to counter consumption by reaction with the solvent. Under these
conditions, carboxylic acids, esters, epoxides, lactones, nitro groups, imides,
amides and nitriles are not reduced. Therefore, reduction of these functional
groups is carried out using stronger reducing agents like lithium aluminum
hydride. Sodium borohydride can, however, be easily modified to a stronger or
more selective reducing agent.275 Examples include the borohydride reduction
step in the industrial synthesis of D-biotin (vitamin H)289 and the selective hydroxy
ester reduction in presence of non-substituted esters, employed in the synthesis
of R-lipoic acid.290 Reports are available for the successful reduction of esters by
utilizing a mixture of sodium borohydride and lithium chloride269a in ethanol.
146
Thus Sodium borohydride is versatile as a reducing agent for both chemo-
and diastereo-selectivity and have been used in the stereoselective reductions.
Sodium borohydride in diglyme in the presence of aluminum chloride267 or sodium
borohydride and ethane dithiol in THF at ambient or reflux temperature is known
to reduce carbonyls belong to esters, acids and even nitriles. The reduction of
esters in non-polar solvents like THF has traditionally required long reaction times
and forcing conditions.
As discussed in section 3.3, the addition of a precise amount of methanol
to the reaction mixture enhances the reactivity of sodium borohydride-THF
system275 and have been successfully used for the reduction of various esters
such as aliphatic, aryl, heteroaryl, α-keto, α-hydroxy esters. It is most likely,
BH3(OMe)- is the active reducing agent involving sodium borohydride and
methanol. It was also reported that hydroxyborohydride BH3OH- has reducing
power relative to lithium aluminium hydride.291 Soai et al. has reported a
convenient method for the rapid and selective reduction of esters of N-protected
amino acid and N- protected peptides with NaBH4 and methanol in THF or t-butyl
alcohol at refluxing conditions. The reaction consumed large excess (tenfold or
higher) of NaBH4 and which was wasted by liberating hydrogen from NaBH4.275
With this back ground, the ester 153 was reduced using sodium
borohydride in methanol (Soai’s condition). Since methanol is known to react
rapidly with NaBH4 at 60 °C, the reaction was carried out at 0 °C. Dry MeOH (3
mL) was added over a period of 20 min to a suspension of 153 and NaBH4 in
THF (Scheme 3.14). After the gas evolution the 11B NMR spectrum of the aliquot
of reaction mixture was recorded (Figure 3.43). The spectrum showed broad
singlet at δ +10 ppm attributable to tetraalkoxyborate ion. When the reaction was
quenched with 2N HCl after 2 h the predominant signal in the 11B NMR spectrum
of the reaction mixture was attributable to trimethoxyborane B(OMe)3 (δ +19
ppm) (Figure 3.44). The reaction mixture was concentrated under vacuum and the
chromatographic purification of the residue over silica gel (60-120 mesh CHCl3:
MeOH) afforded (2R,3R)-3-hydroxymethyl-pentane-1,2,3,5-tetraol (386) in 75%
yield as a colourless oil. 26D][α +2.752 (c 0.40, MeOH). The structure of the
compound was confirmed on the basis of the IR, 1H, 13C NMR and mass spectra.
The IR spectrum displayed absorption bands at 3325 cm-1 (indicate the presence of
147
–OH groups). The 1H NMR spectrum displayed signals at δ 3.7 and 1.8 (multiplets;
due to methylene protons). The 13C NMR spectrum displayed six different signals at
δ δ 76.88, 75.31, 66.01, 63.17, 58.79 and 37.05 which confirmed the number of
carbon atoms of the molecule (Figure 3.46a-e). The DEPT 135 showed –ve signals
at δ 66, 63, 58 and 37 (indicate the presence of -CH2 carbons) and +ve signal at 75
(shows the presence of CH carbon) (Figure 3.47a-e). HRMS (ES+) calculated for
C6H14O5Na: 189.0739, Found: 189.0735 (Figure 3.45)
HO OH
OHHO
HO
386
1. NaBH4, 0 C, THF
2. MeOH, 0 C, 2 h
3. aq HCl
153°
°
Scheme 3.14 Tandem reduction of 153 using NaBH 4 and MeOH
Figure 3.43 11BNMR spectrum of a mixture of 153 and NaBH 4 after the addition of MeOH
148
Figure 3.44 11BNMR spectrum of a solution of 153, NaBH 4 and MeOH after the addition of HCl
Figure 3.45 Single mass analysis of 386
149
IR (Liquid film)
HO OHOH
HOHO
386
Figure 3.46a
1H NMR 400 MHz, Solvent : CD3OD
HO OHOH
HOHO
386
Figure 3.46b
13C NMR 100 MHz, Solvent : CD3OD
HO OHOH
HOHO
386
Figure 3.46c
150
DEPT 135
HO OHOH
HOHO
386
Figure 3.46d
HO OHOH
HOHO
386
Figure 3.46e
The 2D HMQC (Heteronuclear Multiple Quantum Coherence) data was
obtained to support the structure of 386. The assignments of the CH2 carbon shifts
were made on the basis of the 1H-13C short range correlations observed in the 2D
HMQC spectrum which confirms the structure of the polyol 386 (Figure 3.47).
151
Figure 3.47 HMQC obtained for 386
The ester 155 was also subjected to reduction using NaBH4 and MeOH
following the same procedure as that of 153 (Scheme 3.15). The progress of the
reaction was followed by 11B NMR analysis. The 11B NMR spectrum displayed
similar results as in the case of 153. TLC analysis of the reaction mixture after 2 h
indicated the formation of mixture of products 406 and 386 in equal amounts.
This could be explained on the basis of the bulkiness of the isopropyl ester group
present in 155 which in turn reduced the rate of the reduction. Workup of the
reaction mixture and further purification furnished 406 in 40% yield as a
crystalline solid (mp 55-60 °C), { 26D][α +72.78 (c 0.143, Acetone)} and 386 in 35%
yield as a clear oil. The structure of the compounds was confirmed on the basis
of IR, 1H, 13C NMR and mass spectra and compared with the data obtained in
earlier cases.
HO OHOH
HOHO
386
1. NaBH4, 0 oC, THF
2. MeOH, 0 oC, 2 h
3. aq HCl
155
OO O
O
OHHO
406
+
Scheme 3.15 Reduction of 155 using NaBH 4 and MeOH
152
3.4.7 The attempted reduction of C3 carboxylate of dimethyl ( 2S, 3R)-tetrahydro-3-hydroxy-5-oxo-2, 3 furan dicarboxylate (158)
The reduction of the diastereomeric ester 158 was carried out using BMS
and catalytic amount of NaBH4 under the same conditions carried out for the
esters of 6 (Scheme 3.16). The progress of the reaction was followed by 11B
NMR analysis which displayed similar results as in the case of 153 and 155
(Figure 3.50-3.52). The 11B NMR spectrum did not show any signal attributable to
oxyborane intermediate (423) (Figure 3.49). However, the final product contained
was a mixture of alcohols methyl (2S,3S)-3-hydroxy-3-(hydroxymethyl)-5-
oxotetrahydrofuran-2-carboxylate (205) and methyl (2R,3R)-3-hydroxy-2-
(hydroxymethyl)-5-oxotetrahydrofuran-3-carboxylate (420) and was difficult to
purify. It is possible that ester 158 forms both five and six membered
dialkoxyboranes (421 and 422) (Figure 3.48) with BMS due to favorable
stereochemical orientations of the ester and the hydroxy functional groups and
eventually afford a mixture of reduction products. It is impossible to distinguish
the dialkoxyborane intermediates obtained from the BMS reduction of garcinia
and hibiscus esters by 11B NMR spectroscopy as this technique is not sensitive
enough to distinguish between five and six membered dialkoxyboranes.
158BMS,NaBH4
THF
OO OCH3
O
OHHO
OO OH
OCH3HO
O
+
205 420
Scheme 3.16 Reduction of 158 using BMS and catalyti c amount of NaBH 4
When 158 was treated with one equivalent of BMS in THF at 0 °C, the
evolution of one mole equivalent of hydrogen gas was observed. It is inferred that
the hydroxy esters reacted with BMS in a 1:1 stoichiometry to give alkoxy-BH2
(ROBH2) type intermediates (423) or the reaction proceeds through a 3:1
stoichiometry to give an intermediate (424). The 3:1 stoichiometry is expected to
leave 66% of the BMS unreacted after the reaction. However, 11B NMR spectrum
of an aliquot of the reaction mixture did not show any significant signal due to
unreacted BMS or due to the ROBH2 type intermediates (Figure 3.50-3.52).
Apparently, the ester 158 react with BMS in a 1:1 fashion and the initially formed
153
ROBH2 type intermediates quickly transfers a hydride to the proximal ester
carbonyl to give a dialkoxyborane intermediate (421) (Figure 3.48) that was
visible in the 11B NMR spectrum .
OO CO2R
OB
O
H
HOR
OO
O BO
ROOC H
H
OR
421 422
OO
ROOC
O
OB
ORH
Figure 3.48 Five and six membered transition state structures of esters of 7
OO CO2R
OBH2
423
CO2R
OO CO2R
CO2R
O B3
424
Figure 3.49
Figure 3.50 11B NMR spectrum of a solution of 158 immediately aft er the addition of BMS
154
Figure 3.51 11B NMR spectrum of a mixture of 158 and BMS after th e gas evolution
Figure 3.52 11B NMR spectrum of a mixture of 158, BMS and NaBH 4 after quenching
with MeOH
The structure of 205 and 420 was further confirmed by preparing the
acetyl derivatives namely methyl (2S, 3S)-terahydro-3-acetyloxy-3-[(acetyloxy)
methyl]-5-oxo-furan-2-carboxylate (425) and methyl (2R,3R)-terahydro-3-
acetyloxy-2-[(acetyloxy) methyl]-5-oxo-furan-3-carboxylate (426).
155
3.4.8 Conversion to methyl (2 S, 3S)-terahydro-3-acetyloxy-3-[(acetyloxy)methyl]-5-oxo-furan-2-carboxylate (425) and methyl (2R,3R)-terahydro-3-acetyloxy-2-[(acetyloxy)methyl]-5-oxo -furan-3-carboxylate (426)
To confirm the structure of both 205 and 420 obtained during the reduction
of 158, acetylation of the reaction mixture was carried out128 using acetyl chloride
following the same procedure as in the case of 405 using 205 and 420. As
expected, a mixture of the acetyl derivatives 425 and 426 were obtained in
quantitative yield (Scheme 3.17).
OO OCH3
O
OHHO
205 CH3COCl
OO OCH3
O
OCOCH3H3COCO
OO OH
OCH3HO
O
420
OO OCOCH3
OCH3H3COCO
O
+ +
425
426
Scheme 3.17 Acetylation of 205 and 420
IR (liquid film)
OO OCH3
O
OCOCH3H3COCO
OO OCOCH3
OCH3H3COCO
O
+
425
426
Figure 3.53a
156
1H NMR 300 MHz, Solvent : CDCl3
OO OCH3
O
OCOCH3H3COCO
OO OCOCH3
OCH3H3COCO
O
+
425
426
Figure 3.53b
13C NMR 75 MHz, Solvent : CDCl3
OO OCH3
O
OCOCH3H3COCO
OO OCOCH3
OCH3H3COCO
O
+
425
426
Figure 3.53c
157
OO OCH3
O
OCOCH3H3COCO
OO OCOCH3
OCH3H3COCO
O
+
425
426
Figure 3.53d
3.5 Conclusion
In summary, this chapter deals with the precise tuning of boron reagents for
cumulating the syntheses of natural product intermediates by the chemical
modification of (2S, 3S) and (2S, 3R) –tetrahydro-3-hydroxy -5-oxo-2, 3-
furandicarboxylic acids. A systematic selective (site as well as chemo) carbonyl
reduction of the dialkyl (2S, 3S) and (2S, 3R) –tetrahydro-3-hydroxy -5-oxo-2, 3-
furandicarboxylates were carried out, using borane-dimethyl sulfide (BMS) and
sodium borohydride at 0 °C. This regioselective reduction is general and has been
extended to other representative α-hydroxy esters, such as malate and tartrate
diesters. The reduction of 153, using BMS and catalytic amount of sodium
borohydride, furnished a mixture of products formed by the reduction of the
proximal as well as distal ester groups in a ratio ranging from 70:30 to 60:40.
Very good regio-selectivity was observed when 155 was reduced under the same
conditions.
The 11B NMR spectroscopic study revealed the formation of a transient
alkoxy-BH2 (RO-BH2) intermediate initially and its subsequent rapid, uncatalyzed
transfer of a hydride to the proximal ester carbonyl to give a dialkoxyborane
intermediate at 25 °C. The hydride transfer from dialkoxyborane intermediate to
the final trialkoxyborane derivatives is catalyzed either by sodium borohydride or
by sodium methoxide. Alternatively, attempts were made to develop a simple
methodology for trapping the α-hydroxy aldehyde intermediate by the partial
158
reduction of α-hydroxy esters by quenching the dialkoxyborane intermediates with
methanol. The isopropyl mandelate was partially reduced with BMS and
subsequently quenched the reaction mixture with MeOH. The 11B NMR spectrum
showed a doublet at δ 28.99 ppm clearly indicating the formation of an aldehyde.
However, attempts for the isolation of aldehyde as their bisulfite adduct was
unsuccessful. Further studies for the isolation of α-hydroxy aldehydes are
underway. On the other hand, sodium borohydride in methanol at 0 °C behaved
very similar to that of lithium aluminum hydride and tandemly reduced the lactone
and ester carbonyls of both garcinia and hibiscus esters. Under this condition
dimethyl ester of garcinia acid underwent tandem reductions to furnish 386.
However, their analogue 155 furnished a mixture of 406 and 386 in equal amounts.
The 11B NMR spectrum of a solution of sodium borohydride in methanol at 0 °C
showed the signals due to sodium monomethoxyborohydride (NaBH3OMe),
plausible active tandem reducing agent. This active reducing agent is stable only
at or below 0 °C and rapidly decomposes at elevated temperatures. Hence, the
optimum condition for carrying out the reductions involving sodium borohydride in
methanol is at or below 0 °C. Thus the results presented here demonstrate
further insight into the regioselective, partial and tandem reductions of various α-
hydroxy esters employing borohydride reagents.
3.6 Experimental Section
3.6.1 General methods
All operations were carried out under a nitrogen atmosphere. All
glassware, syringes, and needles were oven-dried and cooled under nitrogen gas
before use. THF was freshly distilled from sodium benzophenone ketyl.
Anhydrous MeOH was freshly distilled from calcium hydride. Toluene was
distilled from sodium wire. Sodium methoxide was freshly prepared from
methanol and excess Na metal in anhydrous THF. BMS, BTHF, Sodium
borohydride, diethyl malate, diethyl tartarate, mandelic acid, and malic acid were
commercial products and used without further purification. 1H NMR (400 MHz)
and 13C NMR (100 MHz) were measured on a Brucker AV 400, W M 300 MHz or
Avance 300 MHz spectrometer. Chemical shifts are expressed in parts per million
(ppm) relative to TMS (δ = 0) and coupling constants are reported as Hertz (Hz).
159
Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, p = pentet, br = broad, m = multiplet), coupling constant,
and integration. Boron NMR samples were recorded in CDCl3 at 128.4 MHz
and are reported relative to external standard BF3·Et2O (δ = 0). Melting points
were determined on ‘’Sunbim’’ make electrically heated melting point
apparatus and were uncorrected. IR spectra were recorded using a Shimadzu
IR 470 spectrophotometer as KBr pellets (solids) or thin films (liquids) and
ThermoFisher Is 10 FTIR spectrometer with diamond ATR and are reported as
wavenumber (cm–1). Electron impact mass spectra were recorded on a
Finnigan MAT MS 8230 or Jeol D-300, Jeol-JMS600 HRMS were recorded on
Micromass UK, Q-TOF. Optical rotations were measured on a Rudolph IV
Autopol polarimeter operating at the sodium D line with a 100 mm path length
cell, and are reported as follows: TD][α (concentration (g/100 ml), solvent).
Column chromatography was carried out with Merck product silica (silica
gel 60-120 mesh) and thin layer chromatography was carried out with Merck
product silica (silica gel G for TLC).
3.6.2 Methyl (2 S,3R)-tetrahydro-3-hydroxy-3-(hydroxymethyl)-5-oxo-2 furancarboxylate (204)
A 100 mL two-necked round- bottom flask equipped with a magnetic stir
bar and fitted with a rubber septum was filled with a solution of dimethyl (2S,3S)-
tetrahydro-3-hydroxy-5-oxo-furandicarboxylate, 153 ( 1.0 g, 4.6 mmol) in dry
tetrahydrofuran (10 mL). Through the septum one equivalent of borane dimethyl
sulphide, 10 M (0.8 mL, 4.6 mmol) was added dropwise via syringe over a period
of 10 min at 0 °C with constant stirring. Hydrogen evolution was rapid and
essentially complete at 30 min at 25 °C. After the gas evolution, an aliquot of the
reaction mixture was analyzed by 11B NMR spectroscopy and observed that all
the BMS was disappeared and the appearance of broad singlets at + 21 ppm and
+28 ppm attributable to polymeric trialkoxyboranes, and dialkoxyborane
respectively at 25 °C. The reaction mixture was cooled to 0 °C and powdered
NaBH4 (catalytic) was added in one portion under vigorous stirring. After 20 min
of stirring, the reaction mixture was warmed to 25 °C. The 11B NMR analysis of
an aliquot of reaction mixture displayed the disappearance of signal at δ +28 ppm
and the intensification of signal at δ +21. The reaction mixture was left aside for
160
an additional 2.5 h to ensure the complete reaction. The reaction mixture was
quenched with dry methanol (3mL) (Caution! Hydrogen evolution) and stirred for
further 30 min at room temperature. Again the 11B NMR of the reaction mixture
was analyzed which displayed signals at δ +18 and +10 ppm, corresponds to
trimethoxyborane B(OMe)3 and tetraalkoxyborate ion respectively. Upon
concentration under reduced pressure gave a clear transparent gum. The gum
was dissolved in dry MeOH (5 mL) and again concentrated under reduced
pressure. The operation was repeated to eliminate B (OMe)3 as thoroughly as
possible.
Yield : 70%
26D][α : +27.47 (c 1.02, CHCl3)
IR (liquid film) : νmax 3416, 2959, 1771, 1735, 1634, 951
cm-1
1H NMR (Acetone-d6, 400 MHz) : δ 4.44 (s, 1H), 4.5 (d, 10.4 Hz, 1H), 4.24
(d, 10 Hz, 1H), 3.762 (s, 3H), 3.02 (d, J =
17.6 Hz, 1H), 2.47 (d, J = 17.60 Hz, 1H)
13C NMR (Acetone-d6, 100 MHz) : δ 176.25, 172.6, 79.16, 77.2, 75.29, 52.59,
40.44
11B NMR (CDCl3, 128.37 MHz) : +28(s), +21(bs) [After the gas evolution]
+18(s) [After the addition of NaBH4]
Mass spectrum (EIMS) : 191 (5, M+1), 159 (90), 141 (13), 131 (27),
104(60), 99 (100), 59 (17), 43 (30),
28(20%)
Molecular formula : C7H10O6
Molecular mass : 190.15
3.6.3 Methyl (5 S, 6S) 8-oxo-2-trichloromethyl-1,3,7-trioxa-spiro[4.4]no nane-6-carboxylate (404)
To an ice-cold two-necked round bottom flask fitted with a CaCl2 guard
tude containing methyl (2S,3R)-tetrahydro-3-hydroxy-3-(hydroxymethyl)-5-oxo-2
161
furancarboxylate (204), (1.0 g, 5.26 mmol) anhydrous chloral (0.8 mL, 5.26
mmol) was added dropwise under stirring followed by 2.5 mL of conc. H2SO4.
The reaction mixture was stirred overnight in the dark at room temperature.
Crushed ice (50 g) was added to the reaction mixture, followed by diethyl ether
(50 mL). After stirring for 10 minutes, the ether layer was separated and the
process was repeated thrice (3x20 mL). Combined ether extracts were dried
with Na2SO4 and concentrated. The crude solid obtained was crystallized from
chloroform –hexane (7:3).
Yield : 89%
Mp : 162-164 °C
29D][α
: +13.14 (c 0.25, CHCl3)
IR (KBr pellet) : νmax 3008, 2360, 2341, 1824, 1747, 1712, 1411,
1346, 1203, 1107, 829 cm-1.
1H NMR (CDCl3+ CD3OD, 300 MHz): δ 6.0487 (s, 1H), 4.8 (s, 1H) 4.4762 (d, J
=10.23 Hz, 1H), 4.3727 (d, J =10.23 Hz, 1H),
3.6971 (s, 3H), 2.9686 (d, J = 18.06 Hz, 1H),
2.74505 (d, J = 18.03 Hz, 1H)
13C NMR (CDCl3 + CD3OD, 75 MHz) : δ 174.776, 167.826, 105.161, 97.307, 79.196, 77.426, 76.326, 49.6, 37.556
Mass spectrum (FAB+) : 305.07 (M+1), 176.14 (25), 151 (100), 137.12
(100), 89.39 (56), 77.58 (48), 40.14 (30)
Molecular formula : C9H9Cl3O6
Molecular mass : 319.50
Elemental analysis : Calculated : C: 33.83, H: 2.84
Found : C: 30.81, H: 2.92
3.6.4 Methyl (2 S, 3R)-terahydro-3-acetyloxy-3-acetyloxymethyl-5-oxo-furan-2-carboxylate (405)
Acetyl chloride (2equ.) was added dropwise to the alcohol 204 (1 g, 3.5
mmol) under stirring and the stirring was continued for 12 hours. The reaction
162
mixture was concentrated under vacuum and the compound 405 was extracted in
to dichloromethane.
Yield : 86%
29D][α
: +53.14 (c 0.52, CHCl3)
IR (liquid film) : νmax 3494, 3009, 2969, 1780, 1748, 1452, 1128,
1081, 1013 cm-1
1H NMR
(CDCl3, 300 MHz) : δ 5.3 (s, 1H), 4.6 (d, 2H), 3.9 (s, 3H) 3.0 (d, J =
18.0 Hz, 1H), 2.80 (d, J = 18.0 Hz, 1H), 2.2 (d,
6H)
13C NMR (CDCl3, 75 MHz) : δ 172.16, 169.8, 169.6, 167.02, 83.82,80. 66,
61.59, 53.09, 37.66, 21.49, 20.38
Mass spectrum (EIMS) : 275 (2, M+1), 219 (23), 191 (32), 159 (50), 143
(3), 13 (4.5), 99 (10.5), 90 (15), 59 (6), 43
(15%);
Molecular formula : C11H14O8
Molecular mass : 274.22
Elemental analysis
Found : C 48.28, H 5.20
Calculated : C 48.21, H 5.14
3.6.5 Diisopropyl (2 S,3S)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylate (155)
To a pre-cooled (-5-0 oC) suspension of 152 (1.0 g, 4.4 mmol) in isopropyl
alcohol (10 mL) and thionyl chloride (0.7 mL, 10 mmol) were added. The mixture
was then stirred for 48 h at room temperature. After filtration of the reaction
mixture, pH of the filtrate was adjusted to 7.0, by adding saturated aqueous sodium
bicarbonate and was extracted with chloroform (3X10 mL). The combined extract
upon drying and evaporation gave the compound 155 as pale yellow oil.
163
Yield : 0.5 g (41%)
25D][αααα : +32.0° (c 1.0, CHCl 3)
IR (KBr pellet) : ν max 3454, 2985, 1801, 1752, 1469, 1246, 1214
cm-1
1H NMR (CDCl3, 400 MHz) : δ 5.08 (m, 2H), 4.843 (s, 1H), 3.071 (d, J = 17.6,
1H), 2.822 (d, J = 17.6, 1H), 1.297 (m, 12H)
13C NMR (CDCl3, 100 MHz) : δ 171.59, 169.94, 165.58, 83.92, 78.38, 76.7,
72.41, 70.62, 39.87, 21.66, 21.5, 21.35
Mass spectrum (E.I) : 274 (M+, 7.4), 246 (60.3), 232 (34.2), 216 (21.8),
204 (37.1), 190 (15.8), 174 (23), 162 (52.3), 144
(58.7), 132 (43.6), 117 (12), 98 (15), 76 (52), 42
(100%)
Molecular formula : C12H18O7
Molecular mass : 274.11
Elemental analysis
Found : C, 52.32, H, 6.59
Calculated : C, 52.55, H, 6.57
3.6.6 Isopropyl (2S, 3 R)-terahydro-3-hydroxy-3-hydroxymethyl-5-oxo-furan-2-carboxylate (406)
Reduction was carried out using a solution of diisopropyl (2S,3S)-
tetrahydro-3-hydroxy-5-oxo-furandicarboxylate (155) (1 g, 3.6 mmol) in dry
tetrahydrofuran (10 mL), and borane dimethyl sulphide, 10 M (0.35 mL, 3.65
mmol) and catalytic sodium borohydride as in the case of 153. The progress of
the reaction mixture was followed by the 11B NMR analysis of aliquots of reaction
mixture. The residue obtained was purified through silica column (60-120 mesh,
Ethyl acetate –hexane 7:3) to afford 406 as a colorless crystalline solid.
Yield : 80%
26D][α : +72.78o (c 0.143, Acetone)
Mp : 55-60 °C
164
IR (ATR) : 3443, 2984, 1776.39, 1730, 1467, 1375, 1276,
1237, 1103, 1024 cm-1;
1H NMR (CDCl3, 400 MHz): δ 5.151 (m, 1H), 4.759 (s, 1H), 4.3983 (d, J = 10.44
Hz, 1H), 4.2713 (d, J = 10.39 Hz, 1H), 2.8895 (d, J
= 18 Hz, 1H), 2.6175 (d, J = 18 Hz, 1H) 1.3 (m,
6H).
13C NMR (CDCl3, 100 MHz): δ 174.80, 170.79, 78.08, 76.70, 74.02, 71.64, 38.93, 21.75, 21.73
11B NMR (CDCl3, 128.37 MHz): δ + 28 (s), +22 (s) [After the gas evolution]
+22 (s) [After the addition of NABH4]
Molecular formula : C9H14O6
Molecular mass : 218.08
HRMS (ES+) calculated for C9H14O6 Na: 241.0688, Found: 241.0686.
3.6.7 Methyl (2 S, 3S)-terahydro-3-acetyloxy-3-[(acetyloxy)methyl]-5-oxo -furan-2-carboxylate (425) and Methyl (2 R,3R)-terahydro-3-acetyloxy-2-[(acetyloxy)methyl]-5-oxo-furan-3-carbo xylate (426)
Acetyl chloride (4 equ.) was added dropwise to the mixture of alcohol 205
and 420 (1 gm, 5.26 mmol) under stirring and the stirring was continued for 12
hours. The reaction mixture was concentrated under vacuum and the compounds
425 and 426 were extracted in to dichloromethane.
IR (liquid film) : νmax 3490, 3000, 2969, 1780, 1748, 1452, 1138,
1071, 1010 cm-1
1H NMR (CDCl3, 300 MHz): δ 5.3 (s, 1H), 5.1 (t, 1H), 4.6-4.4 (d, 4H), 3.9 (s, 3H), 3.8 (s, 3H), 3.0 (d, 2H), 2.80 (d, 2H), 2.2-2 (d,12H)
13C NMR (CDCl3, 75 MHz): δ 172.16, 171.0, 169.8, 169.2, 169.6, 168.5, 167.02, 167.5 83.82, 82.2, 80. 66, 79.4, 61.59, 62.3, 53.09, 53.2, 37.66, 38.2, 21.49, 20.38 22.3, 21.8
Mass spectrum (EIMS) : 275 (2, M+1), 219 (23), 191 (32), 159 (50), 143 (3),
13 (4.5), 99 (10.5), 90 (15), 59 (6), 43 (15%)
3.6.8 Reduction of diethyl ( S)-malate
Reduction was carried out using a solution of diethyl (S)-malate (1 gm, 5.2
mmol) in dry toluene (10 mL), and borane dimethyl sulphide, 10 M,(1 equ, 0.45
mL, 5.2 mmol)) and catalytic powdered sodium borohydride at 0 °C as in the
165
case of 153.The progress of the reaction mixture was followed by the 11B NMR
analyzis of aliquots of reaction mixture.
11B NMR (CDCl3, 128.37) : δ +22.42 (s) [After the gas evolution]
22.55, 19.7(s) [After the addition of NaBH4]
3.6.9 Reduction of Diethyl ( R,R)-tartrate
Reduction was carried out using a solution of diethyl (R,R)-tartarate
(1.0 gm, 4.8 mmol) in dry tetrahydrofuran (10 mL), borane dimethyl sulphide
(1 equ,0.459 mL) was added drop wise at 0 °C under stirring, as in the case of
153. The progress of the reaction mixture was followed by the 11B NMR analysis
of aliquots of reaction mixture.
11B NMR (CDCl3, 128.37) : δ +22.42 (s) [After the gas evolution]
22.49 (s) [After the addition of NaBH4]
3.6.10 Procedure for the partial reduction of propa n-2-yl (2 R)-hydroxy(phenyl)ethanoate using BMS and MeOH
Reduction was carried out using a solution of propan-2-yl (2R)-
hydroxy(phenyl)ethanoate (415) (500 mg, 2.6 mmol) in dry THF (5 mL), BMS (1
equiv.0.4 mL, 2.6 mmol) was added drop wise at 0 °C under stirring, as in the
case of 153. The progress of the reaction mixture was followed by the 11B NMR
analysis of aliquots of reaction mixture. After the gas evolution, an aliquot of the
reaction mixture was analyzed by 11B NMR spectroscopy and observed that all
the BMS was disappeared. The reaction mixture was cooled to 0 °C and MeOH
(2 mL) was added over a period of 20 min and stirred for another 30 min. 11B
NMR analysis of aliquots of reaction mixture indicated the presence of aldehydic
intermediate. The solvents were concentrated under vacuum and the reaction
mixture was charged a solution of Na2S2O5 in water and stirred for 4 h. However
the formation of the aldehydic adducts was unsuccessful.
11B NMR (CDCl3, 128.37 MHz) : δ +28.12 (d) [After the gas evolution]
δ 18.7 (s) [After quenching with MeOH]
166
3.6.11 (2R, 3R)-3-hydroxymethyl-pentane-1,2,3,5-tetraol (386)
A 100 mL two necked round- bottom flask equipped with a magnetic stir
bar and fitted with a rubber septum was charged with a suspension of sodium
borohydride (0.19 g, 5 mmol) and dimethyl (2S,3S)-tetrahydro-3-hydroxy-5-oxo-
furandicarboxylate (153) (1.0 g, 4.6 mmol) in dry tetrahydrofuran (10 mL) at 0 °C.
Anhydrous methanol (2 mL) was injected through the septum to this suspension
via syringe over 20 min at the same temperature with constant stirring. The
progress of the reaction was followed by the 11B NMR analysis. The reaction
mixture was stirred for 2 h at 25 °C. The reaction was quenched by the addition
of 2N HCl. The resultant solution was evaporated under vacuum, and the residue
was extracted with CH2Cl2 (5X10 mL). The combined extracts were dried over
anhydrous sodium sulphate. After the evaporation of the solvent under reduced
pressure, the residue obtained was purified through silica gel column (60-120
mesh, CHCl3: MeOH) to give (2R,3R)-3-hydroxymethyl-pentane-1,2,3,5-tetraol
(386) as colourless oil in good yield. The 2D NMR data was recorded to support the
assignment of the structure of the compound.
Yield : 75%
[α]D26 : +2.752° (c 0.40, MeOH)
IR (ATR) : νmax 3307, 2950, 1645, 1416, 1011 cm-1
1H NMR (CD3OD, 400 MHz) : δ 3.711 (m, 7H), 1.8687 (m, 2H)
13C NMR (CD3OD, 100 MHz) : δ 76.88, 75.31, 66.01, 63.17, 58.79, 37.05
11B NMR (CDCl3, 128.37 MHz) : δ + 10 (s), +19 (s).
Molecular formula : C6H14O5
Molecular mass : 166.08
HRMS (ES+) calculated for C6H14O5Na: 189.0739, Found: 189.0735
Recommended